In 1990, he joined The Lancet as an assistant editor and moved to New York as North American editor in 1993. Two years later he returned to the UK to become Editor-in-Chief. He was the first President of the World Association of Medical Editors, and is presently a member of the International Committee of Medical Journal Editors. He has also been president of the US Council of Science Editors (2005-06). He is an honorary professor at the London School of Hygiene and Tropical Medicine and University College London. A book about controversies in modern medicine, Second Opinion, was published in 2003 (Health Wars in the US). He also wrote the Royal College of Physicians report on medical professionalism, Doctors in Society (2005). He is married with one daughter, and lives in London.

At the Time to Go Demo of September 23, 2006, Horton accused American president George Bush and British prime minister Tony Blair of "lies" and "killing children" in Iraq. On October 11, The Lancet published new estimates of the death toll of Iraqi citizens after the US led invasion in 2003, putting it at a total of 655,000. Some supporters of the invasion of Iraq dismissed it for what they claimed was flawed methodology.[1][2][3] Some opponents of the invasion questioned its reliability due to its extreme divergernce from other data on the conflict. [4] Some journals and statistical experts were supportive. Other experts in the field were not convinced, saying the estimates were "high, and probably way too high."[5], and that the authors had published a "misinterpretation of their own figures".[6]
Others were incredulous that the survey could have been performed as reported under such dangerous conditions.[7][8].

Iraq's health minister estimated during a press conference in November 2006 that between 100,000 and 150,000 people had died since the invasion in 2003, based on an estimate of around 100 deaths per day brought to morgues and hospitals during 2006[9], while saying that the Lancet estimates were an "exaggerated number"[10].

U.S. President George W. Bush was asked at a press conference to estimate the number of "civilians, military, police, insurgents (and) translators" that had been killed in Iraq[11] and gave a number of 30,000 deaths, but the White House declined to provide a source for that estimate.

Horton has previously been involved in controversies over the role of the pharmaceutical industry in medicine, the MMR vaccine, the ethics of medical publishing, and global health.[vague]